Several publications and patent documents are referenced in this application in order to describe more fully the state of the art to which this invention pertains. The disclosure of each of these publications is incorporated herein by reference.
Escherichia coli is a common colonizer of the human gastrointestinal tract and although E. coli strains are largely regarded as commensal, some isolates have the potential to cause diseases. Two distinct pathogenic categories of E. coli are recognized depending on whether they cause intestinal or extraintestinal infections. The extraintestinal pathogenic E. coli (ExPEC) group includes human pathogenic strains causing urinary tract infections (UPEC), neonatal meningitis (NMEC) and septicemia. Other ExPEC strains are instead pathogenic for avian species (APEC). The intestinal pathogenic E. coli (InPEC) group includes many pathotypes such as enterotoxigenic (ETEC), enteropathogenic (EPEC), enterohemorrhagic (EHEC), enteroinvasive, adherent invasive, and diffusely adherent E. coli, all causing infections to the human intestinal tract. These pathogenic strains of Escherichia coli are the most common cause of bacterial infections presenting a recurrent global threat that kills over two million of people in the world every year.
Vaccination would undoubtedly be the most cost-effective preventive measure against morbidity and death from pathogenic E. coli strains. However, primary studies have focused attention on the identification of candidates for use in vaccines protective against individual pathogenic categories, for example against UPEC alone or NMEC alone. In an earlier publication based on a comparative genome analysis and using the complete genome sequences of three ExPEC strains (IHE3034, CFT073 and 536), the Inventors identified nine potential vaccine candidates able to confer protection from sepsis (PNAS 2010; 107:20, p 9072-9077).
Whilst vaccines for use against individual diseases or illnesses are useful, it would be desirable to provide broad spectrum vaccines that provide protective immunity in animals, particularly humans, against all, or a large number, of infections caused by E. coli. For example, once vaccinated an individual could be covered or protected against all, or a high percentage, of the different diseases that E. coli can cause. A broadly protective vaccine would be of further benefit due to the spread of antibiotic resistant bacteria (CTX-M β-lactamase and carbepenemases) in hospitals and communities as a whole. However, the development of such a ‘universal’ or ‘pan E. coli’ vaccine is challenging because of the need to selectively prevent against subtypes of E. coli strains that are not normally part of the commensal flora. There is thus a need for improved E. coli vaccines, including a need to move away from crude cell lysates and towards better-defined molecules, and a need to identify antigens that are suitable for inclusion in a ‘universal’ vaccine, particularly antigens that are prevalent among clinically relevant strains without also being found in commensal strains.
In addition, a needle-free or mucosally administered vaccine would be preferable for reasons of improved patient comfort and ease of administration, as well as reducing the risk of contamination and other adverse effects while promoting patient compliance and increasing the safety of vaccination.
The present Inventors have discovered a combination of antigens suitable for use in the preparation of a broad spectrum vaccine against pathogenic E. coli. Surprisingly, the vaccine combination provides protection against disease/illness caused by pathogenic strains of E. coli from both ExPEC and InPEC groups.